title: Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 4.
abstract: The deregulation of Eph/ephrin protein expression has been shown to lead to tumor development and progression. Both mRNA and protein expression analyses using clinical samples have demonstrated that ephrin-A1 is over-expressed in various cancers and positively correlates with a poor prognosis for cancer patients. The prognosis of cancer patients depends on metastasis to distant organs. We previously demonstrated that ADAM12 metalloproteinase cleaved ephrin-A1 and ADAM12-cleaved ephrin-A1 enhanced vascular permeability by degrading VE-cadherin and the EphA2 receptor at the plasma membrane. An increase of soluble ephrin-A1 levels in the serum facilitated tumor cell recruitment to the lungs, which resulted in lung metastasis. We also found that ephrin-A1 was overexpressed in 3LL tumors, a highly metastatic tumor, in mice and TNFα, an authentic positive regulator of ephrin-A1, was not elevated in the tumors, whereas S100A8 was. Moreover, S100A8 induced ephrin-A1 expression mediated by the toll-like receptor 4 (TLR4). S100A8 is known to be an endogenous ligand for TLR4 and its expression was shown to be increased in the lungs at the premetastatic phase. Thus, S100A8 and ephrin-A1 contribute to lung metastasis. Therefore, elucidating the regulation mechanism of ephrin-A1 overexpression is of importance and may lead to the development of therapeutic drugs against tumor growth and metastasis.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan. Electronic address: ieguchi@research.twmu.ac.jp.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Ieguchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Omori
authors.forename: Akiko
authors.initials: A
authors.lastname: Komatsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomita
authors.forename: Atsuko
authors.initials: A
authors.lastname: Deguchi
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D045744:Cell Line, Tumor; D036382:Ephrin-A1 / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D040501:Calgranulin A; D036382:Ephrin-A1; D051197:Toll-Like Receptor 4
keywords: Eph; Ephrin; LLC; Lewis lung carcinoma; MD-2; Metastasis; S100A8; SAA3; TGF; TLR4; VEGF; erythropoietin-producing hepatocellular; myeloid differentiation protein 2; serum amyloid A3; transforming growth factor; vascular endothelial growth factor